Administering aerosols to the lungs via the nose, while convenient, is known to be challenging due to high aerosol depositional losses in the delivery system and extrathoracic airways. In the first phase of this project, we demonstrated that the new excipient enhanced growth (EEG) technique could significantly improve lung delivery efficiency of aerosols administered during non-invasive ventilation and high flow nasal cannula (HFNC) therapy. The EEG approach implements a small particle aerosol containing a hygroscopic excipient to reduce depositional loss in the delivery system, increase aerosol particle size in the airways, and target the site of deposition within the lungs. Using EEG, lung delivery efficiency values were increased from ~1-10% to ~80% together with improved targeting of the small tracheobronchial airways (30-40-fold dose increase) and reduced intersubject variability. These results were based on testing in realistic in vitro airway models and new whole-airway computational fluid dynamics (CFD) simulations. The goal of this translational project is to determine the in vivo lung delivery efficiency of EEG aerosols administered during HFNC therapy using a newly developed and optimized HFNC aerosol delivery unit. A new standalone HFNC therapy aerosol device (delivery unit) will be developed that can simultaneously generate and administer an EEG aerosol. Depositional loss of the medication in the new delivery unit and streamlined nasal cannula interface combined will be <10% of the nebulized dose. Radiolabeled conventional and EEG formulations for mesh nebulization will be developed for human subject testing. The expected lung delivery efficiency of 1-10% with a commercial system will be increased to 80% or greater with the new EEG clinical system. In the human subject study, SPECT-CT images of the lung deposition will be segmented using 2D and 3D approaches and compared with CFD predictions. To accomplish these project goals, the following Aims are proposed: Specific Aim 1. Develop a HFNC aerosol delivery unit for nose-to-lung aerosol administration and optimize performance using concurrent in vitro tests and whole-airway CFD simulations. Specific Aim 2. Characterize the in vitro performance of the radiolabeled aerosol generated using the EEG method and delivery unit and the standard of care method to establish human subject dosimetry. Specific Aim 3. Conduct human subject testing of the HFNC aerosol delivery unit and compare delivery efficiency with current standard of care. Validate whole-airway predictions of the CFD model, and further optimize device performance. Impact. This project will provide a new technique (EEG) and clinical platform (HFNC delivery unit) for high efficiency aerosol delivery, low intersubject variability, and targeted delivery within the lungs for improving the efficacy of existing and new inhaled medications administered using the convenient nose-to-lung route.